Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts
Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts
复制标题
铁调节蛋白2调节小鼠胚胎成纤维细胞从有氧糖酵解到氧化磷酸化的转变
DOI：
10.1073/pnas.1820051116
复制
发表时间：
2019-05-14
影响因子：
11.1
通讯作者：
Li, Kuanyu
中科院分区：
文献类型：
--
作者：
Li, Huihui;Liu, Yutong;Li, Kuanyu
意义铁调节蛋白（IRP）控制细胞铁稳态。Irp 2基因敲除小鼠表现出神经系统疾病的症状，这些症状被认为是由线粒体活性受损引起的。为了探索Irp 2参与线粒体功能，我们研究了Irp 2缺失小鼠胚胎成纤维细胞的代谢途径。我们发现，Irp 2缺陷开关细胞代谢途径从氧化磷酸化（OXPHOS）有氧糖酵解。Irp 2缺陷诱导HIF 1 α和HIF 2 α的表达; HIF 1 α通过上调糖酵解途径相关靶基因增强有氧糖酵解; HIF 2 α抑制线粒体Fe-S生物合成和OXPHOS。这种确定的机制意味着，当Irp 2缺乏时，高能量需求组织（如中枢神经系统）可能会受到影响，导致神经系统疾病。铁调节蛋白（IRP）在线粒体铁稳态和功能中的作用的重要性已被提出。为了了解IRP如何影响线粒体功能，我们使用了Irp 2缺失的小鼠胚胎成纤维细胞（MEFs），发现Irp 2缺失显著诱导了缺氧诱导因子亚基Hif 1 α和Hif 2 α的表达。Hif 1 α的增加上调了其靶基因的表达，增强了糖酵解; Hif 2 α的增加下调了铁硫簇（Fe-S）生物发生相关基因和电子传递链（ETC）相关基因的表达，减弱了线粒体呼吸作用。通过基因敲除或特异性抑制剂抑制Hif 1 α可阻止Hif 1 α靶向基因表达，导致有氧糖酵解减少。通过基因敲低或选择性破坏Hif 2 α和Hif 1 β的异源二聚体来抑制Hif 2 α，通过增强Fe-S生物合成和增加ETC相关基因表达来恢复线粒体ETC和偶联氧化磷酸化（OXPHOS）。我们的研究结果表明，Irp 2调节MEFs中由Hif 1 α和Hif 2 α介导的有氧糖酵解到OXPHOS的代谢转换。
Significance Iron regulatory proteins (IRPs) control cellular iron homeostasis. Irp2 knockout mice show symptoms of neurological disorders, which are considered to result from impaired mitochondrial activity. To explore the involvement of Irp2 in mitochondrial function, we examined the metabolic pathways of Irp2-depleted mouse embryonic fibroblasts. We found that Irp2 deficiency switches cellular metabolic pathways from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. We further revealed that Irp2 deficiency induces the expression of Hif1α and Hif2α; Hif1α enhances aerobic glycolysis by upregulating its target genes related to the glycolytic pathway, and Hif2α suppresses mitochondrial Fe–S biosynthesis and OXPHOS. This identified mechanism implies that high-energy-need tissues, such as the central nervous system, could be affected when Irp2 is deficient, leading to neurological disorders. The importance of the role of iron regulatory proteins (IRPs) in mitochondrial iron homeostasis and function has been raised. To understand how an IRP affects mitochondrial function, we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α. The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron–sulfur cluster (Fe–S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1α by genetic knockdown or a specific inhibitor prevented Hif1α-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2α by genetic knockdown or selective disruption of the heterodimerization of Hif2α and Hif1β restored the mitochondrial ETC and coupled oxidative phosphorylation (OXPHOS) by enhancing Fe–S biogenesis and increasing ETC-related gene expression. Our results indicate that Irp2 modulates the metabolic switch from aerobic glycolysis to OXPHOS that is mediated by Hif1α and Hif2α in MEFs.